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The Journal of Physiology logoLink to The Journal of Physiology
. 2006 May 11;574(Pt 1):85–93. doi: 10.1113/jphysiol.2006.110122

Developing a head for energy sensing: AMP-activated protein kinase as a multifunctional metabolic sensor in the brain

Santosh Ramamurthy 1, Gabriele V Ronnett 1,2
PMCID: PMC1817796  PMID: 16690704

Abstract

The 5′-adenosine monophosphate-activated protein kinase (AMPK) is a metabolic and stress sensor that has been functionally conserved throughout eukaryotic evolution. Activation of the AMPK system by various physiological or pathological stimuli that deplete cellular energy levels promotes activation of energy restorative processes and inhibits energy consumptive processes. AMPK has a prominent role not only as a peripheral sensor of energy balance, but also in the CNS as a multifunctional metabolic sensor. Recent work suggests that AMPK plays an important role in maintaining whole body energy balance by coordinating feeding behaviour through the hypothalamus in conjunction with peripheral energy expenditure. In addition, brain AMPK is activated by energy-poor conditions induced by hypoxia, starvation, and ischaemic stroke. Under these conditions, AMPK is activated as a protective response in an attempt to restore cellular homeostasis. However in vivo, it appears that the overall consequence of activation of AMPK is more complex than previously imagined, in that over-activation may be deleterious rather than neuroprotective. This review discusses recent findings that support the role of AMPK in brain as a multidimensional energy sensor and the consequences of its activation or inhibition under physiological and pathological states.

Introduction

It is well established that a fundamental necessity for survival is the maintenance of energy homeostasis. This requires the presence of appropriate energy sensors that can detect and initiate adaptive changes in response to variations in energy balance. The adenosine monophosphate-activated protein kinase (AMPK) signalling complex is one such sensor. Although previous studies focused on the role of AMPK as cellular metabolic sensor, it is becoming evident that AMPK also plays more complex roles as an organismal metabolic sensor (Carling, 2004).

Functions described for AMPK have included the coordination of anabolic and catabolic metabolic processes in various tissues, including cardiac and skeletal muscle, adipose tissue, pancreas and liver (Kahn et al. 2005). In these tissues, AMPK responds to diverse hormonal, physiological and pathological stimuli, and in turn inhibits ATP-consuming (anabolic) processes and stimulates ATP-generating (catabolic) processes. Thus, the consequences of AMPK activation encompass acute modulation of energy metabolism and chronic changes in gene expression. This is accomplished by phosphorylation and modification of numerous target proteins including biosynthetic enzymes, transporters, transcription factors, ion channels and cell-cycle/signalling proteins (Leff, 2003; Hardie, 2004a, 2005; Hallows, 2005).

It is only within the past several years that the complex physiological role of AMPK in the brain has become evident. In the CNS, it appears that AMPK has a dual function, not only as a cell-autonomous energy sensor, but also as an integrative metabolic sensor. In this regard, AMPK may play a role in the neuronal survival response to energy depletion and as well in hypothalamic control food intake and peripheral energy utilization.

Another emerging concept is that the result of AMPK activation is context specific, i.e. AMPK activation can be either beneficial or deleterious, depending on the tissue, degree of stimulation, or conditions of activation. The differential regulation of AMPK activation is therefore another active area of investigation. Thus, the AMPK pathway and modulation of energy balance through the AMPK system presents an attractive therapeutic target for intervention in many conditions of disordered energy balance, including obesity, type-2 diabetes, and stroke. The scope of this review will be limited to new developments related to AMPK as a metabolic sensor in the brain. Several recent reviews provide further information on the role of the AMPK signalling pathway in the cellular physiology of other systems (Kemp et al. 2003; Hardie, 2004b; Kahn et al. 2005; Luo et al. 2005; Young et al. 2005).

Regulation of AMPK

Functional AMPK is a heterotrimeric kinase complex composed of a catalytic α subunit and regulatory β and γ subunits. In mammals, several alternative genes have been identified for each of the subunits, e.g. α1, α2, β1, β2, γ1, γ2, γ3. Therefore, depending on the tissue or cell type examined, varying combinations of αβγ heterotrimers are possible (Stapleton et al. 1996). The subunit composition in a specific tissue or cell type may be important to the role that AMPK plays in regard to energy sensing in that particular tissue. Several studies have examined AMPK subunit expression in the brain and are discussed in further detail below (Turnley et al. 1999; Culmsee et al. 2001).

AMPK catalytic activity is enhanced not only by AMP binding, but also by α subunit phosphorylation by an upstream kinase (Davies et al. 1995; Hawley et al. 1996; Stein et al. 2000). The search for the identity of the upstream kinases that phosphorylate and activate AMPK has been a long one (Witters et al. 2006). However, the identification of these kinases may provide further insight into the tissue-specific as well as brain-specific regulation of AMPK. Initially it was shown that the Peutz–Jeghers syndrome tumour suppressor gene, LKB1, is an AMPK kinase (Hawley et al. 2003; Woods et al. 2003). Subsequently, studies in various cell-lines, tissues and in vivo models demonstrated the physiological importance of activation of the LKB1-AMPK signalling pathway (Shaw et al. 2004, 2005; Jones et al. 2005; Sakamoto et al. 2005). However, despite the fact that LKB1 has been reported to be widely expressed in various tissues, its role in brain AMPK regulation has not yet been elucidated (Rowan et al. 2000).

Most recently, three groups independently reported that calcium/calmodulin-dependent protein kinase β (CaMKKβ) is an additional upstream kinase of AMPK (Hawley et al. 2005; Hurley et al. 2005; Woods et al. 2005). Although the precise physiological relevance of this activation is unclear, several possibilities exist. Since CaMKKβ is a Ca2+-activated kinase, it is possible that stimuli that elevate intracellular calcium levels (e.g. extracellular ligands, hormones) are capable of eliciting AMPK activation. This may be a predominant upstream pathway of AMPK activation in tissues with high CaMKKβ expression, such as the brain (Anderson et al. 1998; Sakagami et al. 1998). Another intriguing possibility is that in tissues where both CaMKKβ and LKB1 are expressed, different stimuli (e.g. hormonal versus metabolic) may elicit AMPK activation through divergent upstream kinases and mediate different physiological responses. Together, these new findings open many avenues of research into mechanisms of AMPK regulation in the brain and further experimentation is needed to test these possibilities.

AMPK expression in the brain

Neurons

While early studies demonstrated expression of AMPK in numerous tissues, only recently has brain-specific AMPK been examined in detail (Gao et al. 1995; Stapleton et al. 1996). Initially, immunohistochemical and Northern Blot analysis demonstrated the expression of AMPK subunits in the embryonic and postnatal mouse brain (Turnley et al. 1999). The authors found that AMPK subunits exhibited a predominant neuronal localization with some expression in activated astrocytes and oligodendrocytes. Notably, the α2 isoform was expressed at higher levels than the α1 isoform, and localized to the nucleus of neurons in many brain regions. The β1 subunit also showed a preferential nuclear localization, whereas the β2 was mainly cytosolic. The γ1 subunit displayed differential region-specific nuclear expression, while the γ2 subunit was primarily cytosolic. Additionally, the authors observed that AMPK expression was especially high in cerebellar Purkinje neurons and hippocampal pyramidal neurons, regions that had previously been shown to exhibit high metabolic rate and glucose utilization (Pertsch et al. 1988). A subsequent immunohistochemical study of rat embryonic and adult cortex and hippocampus as well as dissociated rat hippocampal neurons detected substantial α1 subunit expression in addition to α2, β1, β2 and γ1 subunits (Culmsee et al. 2001). Lastly, work from our laboratory has demonstrated that AMPK catalytic subunits are present in the hypothalamic arcuate nucleus (ARC), colocalize with neuropeptide Y (NPY) expressing neurons, and play a role in feeding control (see below) (Kim et al. 2004a). Collectively these studies provide evidence that AMPK catalytic and regulatory subunits are differentially expressed in various brain and subcellular regions. It would be of great interest to determine whether AMPK has different roles in different brain regions and whether region-specific AMPK subunit expression contributes to potentially different physiological functions. These are interesting ideas that have not yet been tested experimentally.

Glial cells

Previously, several groups have also reported the expression of AMPK in oligodendrocytes and astrocytes in culture (Moore & Brophy, 1994; Cox et al. 1997). Separate studies showed that AMPK in astrocytes plays a role in ketogenesis and in the prevention of apoptosis (Blazquez et al. 1999; Blazquez et al. 2001). However, in our recent work, AMPK expression was confined to neurons and was undetectable in glial cell types both in culture and in vivo (Landree et al. 2004; McCullough et al. 2005). This discrepancy may derive not only from differences in culture conditions, but also from differences between in vitro culture and in vivo conditions. Interestingly, it was found in vivo that AMPK is up-regulated in activated astrocytes during reactive gliosis (Turnley et al. 1999). The fact that astrocytes in long-term cell culture exhibit similarities to reactive astrocytes supports the earlier in vitro findings of astrocyte AMPK expression (Cox et al. 1997). Thus, it is likely the astrocytic AMPK may play an important role under pathophysiological conditions. Clearly, additional studies are required to investigate the mechanisms of this cell-specific regulation of AMPK expression under normal and pathological conditions.

AMPK and energy balance: role in feeding

Although studies had reported expression of AMPK in the brain, its physiological function remained unclear until recently. In peripheral tissues, AMPK was hypothesized to function as a ‘cellular fuel gauge’ (Hardie & Carling, 1997). Several groups demonstrated that a physiological stimulus such as exercise (skeletal muscle contraction) induces AMPK activation and promotes glucose uptake and fatty acid oxidation (Winder & Hardie, 1996; Merrill et al. 1997; Vavvas et al. 1997; Hayashi et al. 1998; Mu et al. 2001). Additionally, adipocyte-derived hormones (adipokines) such leptin and adiponectin increased AMPK activity in muscle and liver to promote fatty acid oxidation and/or glucose utilization (Minokoshi et al. 2002; Yamauchi et al. 2002). Thus, it became apparent that AMPK could be activated not only by physiological stimuli but also by hormonal cues to restore bodily energy homeostasis. Therefore, due to this role as a peripheral energy status sensor, it was postulated that AMPK might have a more global role in the hypothalamus as a central integrator of energy status and master controller of feeding behaviour (Ruderman et al. 2003). In this regard, several independent studies (discussed below) have demonstrated that hypothalamic AMPK is responsive to circulating hormones (orexigenic and anorexigenic), alterations in cellular energy levels, as well as nutrient cues. In turn, modulation of AMPK activity initiates a series of events leading to alterations in feeding behaviour (Fig. 1). Although many of these studies have utilized pharmacological or genetic approaches to alter AMPK activity, collectively they provide insight into the physiological relevance of this pathway. Thus, the fact that AMPK has the capability to respond to multiple cues makes it a likely candidate to act as a physiologically relevant ‘signal integrator’ and output controller under normal as well as pathological conditions.

Figure 1. Mechanisms of AMPK regulation in the brain.

Figure 1

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In the hypothalamus, positive energy balance signals inhibit AMPK phosphorylation, whereas negative energy balance signals stimulate AMPK phosphorylation and activation. These signals are integrated and proceed through alterations in either the LKB1 or CaMKKβ pathways. A series of metabolic and gene transcription events is initiated, ultimately leading to an inhibition or stimulation of the feeding response. In the cortex or hippocampus, physiological or pathological stimuli either inhibit or activate AMPK. Low levels of AMPK activation may elicit compensatory metabolic and survival pathways. Pathological stimuli such as ischaemic stroke may overactivate AMPK and compensatory pathways ultimately leading to metabolic failure and cell death.

Anorexigenic and orexigenic hormones

An initial report in rats demonstrated that intraperitoneal (i.p.) injection of the anorexigenic hormone leptin reduced hypothalamic AMPK activity (Andersson et al. 2004). Consistent with these findings, a separate study showed that injection of mice with leptin produced a decrease in AMPK α2 activity in paraventricular and arcuate hypothalamic feeding centres (Minokoshi et al. 2004). A similar response was found with intracerebroventricular (i.c.v.) injection of other anorexigenic stimuli, such as insulin, glucose, the melanocortin receptor agonist, MT-II, or re-feeding after overnight fasting. To provide a link between hormonal regulation of hypothalamic AMPK and feeding behaviour, the authors of this latter study used a genetic approach, expressing constitutively active or dominant negative AMPK α2 constructs in hypothalamic feeding nuclei. In these experiments it was found that a reduction in AMPK activity was required for the central anorexigenic effects of leptin and that a reduction in hypothalamic AMPK activity is sufficient to reduce body weight and food intake (Minokoshi et al. 2004).

In contrast, it has also been observed that elevation of AMPK activity is involved in the feeding response to orexigenic stimuli. Thus, either direct hypothalamic injection of the pharmacological AMPK activator 5-amino-4-imidazole carboxamide riboside (AICAR), or expression of a constitutively active AMPK is sufficient to cause an increase in food intake and body weight (Andersson et al. 2004; Minokoshi et al. 2004). Similarly, injection of orexigenic hormones such as ghrelin and cannabinoids leads to an elevation of hypothalamic AMPK activity, suggesting that this may be a mechanism to mediate increased feeding (Andersson et al. 2004; Kirkham, 2005; Kola et al. 2005). Lastly, expression of a constitutively active AMPK increased fasting-induced expression of the orexigenic hormones neuropeptide Y (NPY) and agouti-related peptide, whereas a dominant-negative AMPK suppressed expression of these hormones under ad libitum fed conditions (Minokoshi et al. 2004). Thus, hypothalamic AMPK activation can be reciprocally regulated by orexigenic and anorexigenic stimuli and coordinate the feeding response. This is mostly likely due to direct action upon hypothalamic targets as receptors for these hormones were shown to localize to specific neuronal populations (Williams et al. 2001). However, the mechanism by which hormones modulate hypothalamic AMPK activity and elicit changes in feeding behaviour is not yet known. This may involve changes in hypothalamic gene expression as well as alterations in neuronal activity and signalling.

Cellular energy status

Independently, work from our group demonstrated a role for hypothalamic AMPK in the control of food intake by pharmacological manipulation of cellular energy pathways. While developing agents to modulate fatty acid metabolism, we found that mice treated with C75, a synthetic fatty acid synthase (FAS) inhibitor/carnitine palmitoyltransferase (CPT-1) stimulator, exhibited a dramatic reduction in food intake and body weight (Loftus et al. 2000). Subsequently it was determined using dissociated rat cortical neurons in vitro that C75 treatment causes an increase in both fatty acid and glucose oxidation and intracellular ATP levels. This was accompanied by a transient rise and a prolonged inhibition of AMPK activity, resulting in the production of an ‘energy-rich’ state (Landree et al. 2004). Thus, through modulation of FAS and CPT-1 activities, neuronal energy levels were altered to affect AMPK activity, probably through a change in the perception of neuronal energy balance. On the basis of these data, in vivo studies were performed to investigate the connection between alterations of hypothalamic AMPK activity/energy balance and C75-induced anorexia and weight loss. It was found that either i.p. or i.c.v. injection of C75 in mice induced a rapid reduction in hypothalamic phospho-AMPK levels (Kim et al. 2004a). Treatment with C75 also produced an increase in ATP levels in hypothalamic neuronal cultures. Additionally, i.c.v. injection of AICAR increased food intake (consistent with Andersson et al. 2004), whereas i.c.v. administration of the AMPK inhibitor, compound C, substantially reduced food intake in mice. Furthermore, administration of AICAR with C75 reversed not only the C75-mediated inhibition of AMPK phosphorylation, but also the anorexigenic effects of C75. These studies also showed that C75 treatment was associated with decreased hypothalamic cyclic AMP response element binding protein (CREB) phosphorylation and reduced orexigenic NPY gene transcription in the arcuate nucleus, whereas the opposite was observed with AICAR treatment. Based on these data, it was suggested that changes in hypothalamic energy flux, e.g. by changes in ATP/AMP levels induced by long-term fasting or modulation of fatty acid metabolism, could be monitored by AMPK and transduced to changes in gene expression to control whole organism energy balance, i.e. by altering feeding behaviour. It remains to be resolved whether AMPK kinase can respond to transient physiological fluctuations, or whether it indeed serves as a master sensor that is only activated with more extreme changes in energy levels.

Fatty acids and glucose

Several groups have also investigated the effects of circulating nutrients such as fatty acids and glucose on AMPK activation and feeding. Initially, the effect of the naturally occurring fatty acid α-lipoic acid, a cofactor of mitochondrial respiratory enzymes, on obesity and feeding was studied (Kim et al. 2004b). It was found in rats, that injection of α-lipoic acid or administration of a diet containing α-lipoic acid, produced a significant reduction in body weight and food intake. It was determined that these anorexigenic effects were mediated by a reduction in hypothalamic AMPK activity. Interestingly, it was found that α-lipoic acid did not affect hypothalamic neuropeptide expression. Therefore, it would be of considerable interest to determine how α-lipoic acid elicits its anorexigenic effects through AMPK activation, perhaps though a central gene transcription-independent mechanism. However, the authors did observe an increase in peripheral energy expenditure, an effect that was associated with increased expression of uncoupling protein-1 (UCP-1) in adipose tissue. Although it is likely that activation of peripheral AMPK and subsequent stimulation of energy expenditure is involved in this effect, a definitive molecular mechanism remains to be further elucidated.

AMPK has also been suggested to be a glucose sensor. In this regard, it was shown in cell lines and ex vivo hypothalamic tissue that AMPK activity is stimulated by low glucose levels and that direct AMPK activation up-regulates orexigenic agouti-related peptide expression (Lee et al. 2005). This study also demonstrated that small changes in hypothalamic glucose levels in the physiological range of 1–5 mm altered cellular ATP levels sufficiently to induce AMPK activation and gene expression. Another recent study suggested a potential role for ventromedial hypothalamic AMPK in the counteregulatory response to insulin-induced hypoglycaemia in vivo (McCrimmon et al. 2004). In this study it was found that injection of AICAR reduced the amount of infused glucose required for hyperinsulinaemic–hypoglycaemic clamp conditions. The authors attributed this effect to stimulation of hepatic glucose production via a non-hormonal signalling mechanism. Together these studies raise the possibility that ‘glucose-sensing neurons’ in various hypothalamic regions, which have been shown to respond to small alterations in glucose levels and change their firing rate, may utilize the AMPK system in their signalling pathway (Levin, 2001; Levin et al. 2004). These hypothalamic neurons have also been shown to respond to circulating hormones as well as glucose (Spanswick et al. 1997, 2000; Wang et al. 2004). However, a definite role for AMPK in the regulation of hypothalamic neuronal excitability and firing rate has not yet been shown in response to any stimulus. It is also unclear whether glucose-sensing is directly related to alterations in food intake, or more likely whether it is one of many signals that are integrated by hypothalamic feeding centres (Levin et al. 2004). However, a recent study showed that abnormal elevation of hypothalamic AMPK contributes to hyperphagia in a diabetic rat model (Namkoong et al. 2005). Further studies are required both in vivo and in vitro, to investigate the physiological role of AMPK and the connection between glucose-sensing and feeding behaviour.

Other feeding mechanisms

In addition to AMPK, other central mechanisms of food intake regulation have been suggested (Ruderman et al. 1999, 2003). In this regard, it has been proposed that inhibition of the enzyme carnitine palmitoyltransferase-1 (CPT-1) by accumulation of either long-chain (oleic acid) or short-chain fatty acids/malonyl-CoA in the hypothalamus causes a reduction in food intake (Obici et al. 2003; Lane et al. 2005). CPT-1 is the enzyme that controls the entry of long chain-fatty acyl-CoAs into the mitochondria to undergo β-oxidation. This hypothesis (originally derived from studies of muscle), suggests that an increase in hypothalamic fatty acids signals that energy stores are sufficient and subsequently inhibits the feeding response. Interestingly, it was found that the anorexigenic compound C75, also stimulates CPT-1 activity and fatty acid oxidation in addition to inhibiting fatty acid synthesis (Thupari et al. 2002; Landree et al. 2004). Thus, the interplay between malonyl-CoA, CPT-1 and feeding behaviour is complicated. Because the precise mechanism of these effects is not yet identified, further study is needed into the role of CPT-1 activity, as well as its possible regulation by AMPK in hypothalamic energy perception.

AMPK and energy balance: role in neuroprotection

In addition to being regulated by hormones and fluxes in cellular ATP/AMP levels, AMPK is also activated by cellular stresses such hypoxia, ischaemia, oxidative and nitrosative stresses, as well as and metabolic poisons (Hardie, 2004a). Furthermore, given the high metabolic demands of the brain and its relative intolerance of ischaemia, hypoxia, as well as energy depletion, it is very likely that AMPK activity plays an important role in brain energy homeostasis. Despite this fact, the function of AMPK in neuronal energy metabolism, either under normal or pathological conditions, has not been extensively studied. However, some clues regarding the role of AMPK in neuroprotection are emerging (Fig. 1).

Culmsee et al. (2001) initially reported, using isolated hippocampal neurons, that AMPK activation with AICAR provided cytoprotection following glucose deprivation, glutamate excitotoxicity, Aβ peptide exposure (an oxidative stress), or sodium cyanide treatment (a mitochondrial toxin). Additionally, depletion of AMPK α subunits using antisense RNAs abrogated the protective effect of AICAR stimulation. Therefore, according these treatment protocols, it was shown that AMPK activation promotes neuronal survival at least under in vitro conditions. It is unclear whether these neuronal insults activated AMPK by themselves or what the effectors of AMPK-mediated neuroprotection are. Other work has shown that AMPK activation can have either pro-survival or pro-apoptotic effects in various brain cell-lines/types under different experimental conditions (Blazquez et al. 2001; Garcia-Gil et al. 2003; Jung et al. 2004). It is possible that differential AMPK subunit expression, activation, or effectors, may explain these discrepancies. Therefore, additional studies are required to elucidate the molecular mechanisms and consequences of AMPK activation or inhibition in the setting of these varied conditions and injury models as well their relevance to in vivo physiology.

Further insight into the function of AMPK under one CNS injury model, i.e. cerebral ischaemia, was provided by our most recent work (McCullough et al. 2005). In these studies, using an in vivo mid-cerebral artery occlusion (MCAO) and reperfusion system, it was found that AMPK was phosphorylated in cortical tissue within 90 min of vessel occlusion. Similar results were observed in hippocampal slice cultures subjected to 2 h of oxygen glucose deprivation (OGD), an in vitro stroke model. A global activation of AMPK was seen following these insults, suggesting that this was a compensatory response to facilitate the restoration of falling ATP levels. Surprisingly, administration of AICAR exacerbated stroke damage, whereas the AMPK inhibitor, compound C, provided neuroprotection. Additionally, the FAS inhibitor/CPT-1 stimulator C75, a compound known to increase neuronal ATP levels and inhibit AMPK, was also neuroprotective in this stroke model. It was also noted that mice deficient in neuronal nitric oxide synthase (nNOS) had smaller infarcts and lower AMPK phosphorylation levels than their wild-type counterparts, suggesting that excessive nitric oxide (NO) or peroxynitrate (ONOO) production may contribute to AMPK activation in stroke. Collectively, these data suggest that in the setting of ischaemia and reperfusion injury, AMPK activation is detrimental to neuronal survival, and that prevention of AMPK activity may be neuroprotective.

This finding illustrates that the consequences of AMPK activation under stress may be more complex than previously imagined, and the outcome of AMPK activation may be cell or tissue specific. Several recent studies have suggested that AMPK activation in the heart following ischaemia and reperfusion is cardioprotective (Marsin et al. 2000; Russell et al. 2004). These groups found that following injury, AMPK activation promotes glucose uptake and glycolysis, and limits apoptosis and cell damage. Whereas in peripheral tissues, activation of AMPK may inhibit energy-consumptive processes and promote energy-generating and survival pathways in an attempt to restore homeostasis, similar mechanisms may not exist or fail to operate in the brain. For example, following ischaemic stroke, a series of detrimental events is initiated, including a decrease in protein synthesis, disruption of membrane integrity and excessive intracellular Ca2+ influx (excitotoxicity) (Johnston, 2005). Although it is not known how AMPK is activated under these conditions, it is possible that Ca2+ influx and subsequent activation of CaMKKβ is a major pathway. Despite the fact that this kinase has not been implicated in ischaemic neuronal death, further experiments are required to test this notion.

Another hallmark of ischaemic injury is NO/ONOO/superoxide overproduction and oxidative stress (Lewen et al. 2000). In this regard, it has been demonstrated that astrocytes and neurons may respond differently to these insults, in particular to NO exposure (either derived from eNOS or nNOS) (Almeida et al. 2001, 2004). Whereas NO induces inhibition of mitochondrial respiration, induction of AMPK activity, and restoration of glycolysis and improved survival in astrocytes, a similar response is not observed in neurons due to their low expression of 6-phosphofructo-2-kinase (PFK2), a target of AMPK phosphorylation (Almeida et al. 2004). As a consequence, numerous compensatory energy-consuming neuronal pathways are activated which may further exacerbate cellular dysfunction. Thus, it is plausible that excessive neuronal AMPK activation when oxygen and glucose substrates are lacking may induce a detrimental ‘metabolic failure-like’ state. Under these conditions, pharmacological AMPK inhibition would be beneficial to neuronal survival. Therefore, much further work is necessary to investigate the mechanisms of AMPK activation in ischaemic injury in vivo and the effect of alterations in neuronal energy status under these conditions.

Conclusions

Recent years have witnessed an expanded interest in the roles of AMPK in numerous physiological systems. Additional methods of AMPK regulation have been discovered. Whereas, once it was thought to be regulated primarily by cellular AMP/ATP and nutrient levels, it is now clear that additional pathways for activation of AMPK are possible. These various stimuli include hormones, physiological state, as well as pathological events. This complexity of function is evident in the brain where AMPK is a coordinator of whole body metabolism through feeding behaviour as well as local regulator of neuronal homeostasis. In hypothalamus, the role of hormonal control of AMPK activation is an exciting area of research with many unanswered questions. What are the precise signalling mechanisms that mediate orexigenic and anorexigenic hormone action in the hypothalamus to coordinate the feeding response? Additionally, the molecular basis for divergent AMPK regulation in the brain and periphery, tissue/cell-specific AMPK regulation, and physiological/pathological AMPK activation remains to be elucidated. It would be intriguing to study the relative importance of the LKB1 or the CaMKKβ pathways in these varied conditions in the brain. Additional AMPK kinases may remain to be discovered, which will provide clues to additional AMPK functions. Determination of the significance of differential tissue-specific or subcellular (cytosolic versus nuclear) localization of AMPK subunits may also provide insight into AMPK regulation. Whereas nuclear AMPK activation may elicit long-term gene expression changes, cytosolic AMPK may be involved in the modulation of more immediate metabolic and homeostatic responses. Together, additional insight into AMPK physiology in the brain as well as the consequences of its modification may suggest novel therapeutic targets for obesity, type-2 diabetes, stroke and neurodegeneration.

References

  1. Almeida A, Almeida J, Bolanos JP, Moncada S. Different responses of astrocytes and neurons to nitric oxide: the role of glycolytically generated ATP in astrocyte protection. Proc Natl Acad Sci U S A. 2001;98:15294–15299. doi: 10.1073/pnas.261560998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Almeida A, Moncada S, Bolanos JP. Nitric oxide switches on glycolysis through the AMP protein kinase and 6-phosphofructo-2-kinase pathway. Nat Cell Biol. 2004;6:45–51. doi: 10.1038/ncb1080. [DOI] [PubMed] [Google Scholar]
  3. Anderson KA, Means RL, Huang QH, Kemp BE, Goldstein EG, Selbert MA, Edelman AM, Fremeau RT, Means AR. Components of a calmodulin-dependent protein kinase cascade. Molecular cloning, functional characterization and cellular localization of Ca2+/calmodulin-dependent protein kinase kinase β. J Biol Chem. 1998;273:31880–31889. doi: 10.1074/jbc.273.48.31880. [DOI] [PubMed] [Google Scholar]
  4. Andersson U, Filipsson K, Abbott CR, Woods A, Smith K, Bloom SR, Carling D, Small CJ. AMP-activated protein kinase plays a role in the control of food intake. J Biol Chem. 2004;279:12005–12008. doi: 10.1074/jbc.C300557200. [DOI] [PubMed] [Google Scholar]
  5. Blazquez C, Geelen MJ, Velasco G, Guzman M. The AMP-activated protein kinase prevents ceramide synthesis de novo and apoptosis in astrocytes. FEBS Lett. 2001;489:149–153. doi: 10.1016/s0014-5793(01)02089-0. [DOI] [PubMed] [Google Scholar]
  6. Blazquez C, Woods A, De Ceballos ML, Carling D, Guzman M. The AMP-activated protein kinase is involved in the regulation of ketone body production by astrocytes. J Neurochem. 1999;73:1674–1682. doi: 10.1046/j.1471-4159.1999.731674.x. [DOI] [PubMed] [Google Scholar]
  7. Carling D. The AMP-activated protein kinase cascade – a unifying system for energy control. Trends Biochem Sci. 2004;29:18–24. doi: 10.1016/j.tibs.2003.11.005. [DOI] [PubMed] [Google Scholar]
  8. Cox SE, Pearce B, Munday MR. AMP-activated protein kinase in astrocytes. Biochem Soc Trans. 1997;25:S583. doi: 10.1042/bst025s583. [DOI] [PubMed] [Google Scholar]
  9. Culmsee C, Monnig J, Kemp BE, Mattson MP. AMP-activated protein kinase is highly expressed in neurons in the developing rat brain and promotes neuronal survival following glucose deprivation. J Mol Neurosci. 2001;17:45–58. doi: 10.1385/JMN:17:1:45. [DOI] [PubMed] [Google Scholar]
  10. Davies SP, Helps NR, Cohen PT, Hardie DG. 5′-AMP inhibits dephosphorylation, as well as promoting phosphorylation, of the AMP-activated protein kinase. Studies using bacterially expressed human protein phosphatase-2Cα and native bovine protein phosphatase-2AC. FEBS Lett. 1995;377:421–425. doi: 10.1016/0014-5793(95)01368-7. [DOI] [PubMed] [Google Scholar]
  11. Gao G, Widmer J, Stapleton D, Teh T, Cox T, Kemp BE, Witters LA. Catalytic subunits of the porcine and rat 5′-AMP-activated protein kinase are members of the SNF1 protein kinase family. Biochim Biophys Acta. 1995;1266:73–82. doi: 10.1016/0167-4889(94)00222-z. [DOI] [PubMed] [Google Scholar]
  12. Garcia-Gil M, Pesi R, Perna S, Allegrini S, Giannecchini M, Camici M, Tozzi MG. 5′-Aminoimidazole-4-carboxamide riboside induces apoptosis in human neuroblastoma cells. Neuroscience. 2003;117:811–820. doi: 10.1016/s0306-4522(02)00836-9. [DOI] [PubMed] [Google Scholar]
  13. Hallows KR. Emerging role of AMP-activated protein kinase in coupling membrane transport to cellular metabolism. Curr Opin Nephrol Hypertens. 2005;14:464–471. doi: 10.1097/01.mnh.0000174145.14798.64. [DOI] [PubMed] [Google Scholar]
  14. Hardie DG. The AMP-activated protein kinase pathway – new players upstream and downstream. J Cell Sci. 2004a;117:5479–5487. doi: 10.1242/jcs.01540. [DOI] [PubMed] [Google Scholar]
  15. Hardie DG. AMP-activated protein kinase: a master switch in glucose and lipid metabolism. Rev Endocr Metab Disord. 2004b;5:119–125. doi: 10.1023/B:REMD.0000021433.63915.bb. [DOI] [PubMed] [Google Scholar]
  16. Hardie DG. New roles for the LKB1→AMPK pathway. Curr Opin Cell Biol. 2005;17:167–173. doi: 10.1016/j.ceb.2005.01.006. [DOI] [PubMed] [Google Scholar]
  17. Hardie DG, Carling D. The AMP-activated protein kinase – fuel gauge of the mammalian cell. Eur J Biochem. 1997;246:259–273. doi: 10.1111/j.1432-1033.1997.00259.x. [DOI] [PubMed] [Google Scholar]
  18. Hawley SA, Boudeau J, Reid JL, Mustard KJ, Udd L, Makela TP, Alessi DR, Hardie DG. Complexes between the LKB1 tumor suppressor, STRADα/β and MO25α/β are upstream kinases in the AMP-activated protein kinase cascade. J Biol. 2003;2:28. doi: 10.1186/1475-4924-2-28. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Hawley SA, Davison M, Woods A, Davies SP, Beri RK, Carling D, Hardie DG. Characterization of the AMP-activated protein kinase kinase from rat liver and identification of threonine 172 as the major site at which it phosphorylates AMP-activated protein kinase. J Biol Chem. 1996;271:27879–27887. doi: 10.1074/jbc.271.44.27879. [DOI] [PubMed] [Google Scholar]
  20. Hawley SA, Pan DA, Mustard KJ, Ross L, Bain J, Edelman AM, Frenguelli BG, Hardie DG. Calmodulin-dependent protein kinase kinase-β is an alternative upstream kinase for AMP-activated protein kinase. Cell Metab. 2005;2:9–19. doi: 10.1016/j.cmet.2005.05.009. [DOI] [PubMed] [Google Scholar]
  21. Hayashi T, Hirshman MF, Kurth EJ, Winder WW, Goodyear LJ. Evidence for 5′-AMP-activated protein kinase mediation of the effect of muscle contraction on glucose transport. Diabetes. 1998;47:1369–1373. doi: 10.2337/diab.47.8.1369. [DOI] [PubMed] [Google Scholar]
  22. Hurley RL, Anderson KA, Franzone JM, Kemp BE, Means AR, Witters LA. The Ca2+/calmodulin-dependent protein kinase kinases are AMP-activated protein kinase kinases. J Biol Chem. 2005;280:29060–29066. doi: 10.1074/jbc.M503824200. [DOI] [PubMed] [Google Scholar]
  23. Johnston MV. Excitotoxicity in perinatal brain injury. Brain Pathol. 2005;15:234–240. doi: 10.1111/j.1750-3639.2005.tb00526.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Jones RG, Plas DR, Kubek S, Buzzai M, Mu J, Xu Y, Birnbaum MJ, Thompson CB. AMP-activated protein kinase induces a p53-dependent metabolic checkpoint. Mol Cell. 2005;18:283–293. doi: 10.1016/j.molcel.2005.03.027. [DOI] [PubMed] [Google Scholar]
  25. Jung JE, Lee J, Ha J, Kim SS, Cho YH, Baik HH, Kang I. 5-Aminoimidazole-4-carboxamide-ribonucleoside enhances oxidative stress-induced apoptosis through activation of nuclear factor-κB in mouse Neuro 2a neuroblastoma cells. Neurosci Lett. 2004;354:197–200. doi: 10.1016/j.neulet.2003.10.012. [DOI] [PubMed] [Google Scholar]
  26. Kahn BB, Alquier T, Carling D, Hardie DG. AMP-activated protein kinase: ancient energy gauge provides clues to modern understanding of metabolism. Cell Metab. 2005;1:15–25. doi: 10.1016/j.cmet.2004.12.003. [DOI] [PubMed] [Google Scholar]
  27. Kemp BE, Stapleton D, Campbell DJ, Chen ZP, Murthy S, Walter M, Gupta A, Adams JJ, Katsis F, Van Denderen B, Jennings IG, Iseli T, Michell BJ, Witters LA. AMP-activated protein kinase, super metabolic regulator. Biochem Soc Trans. 2003;31:162–168. doi: 10.1042/bst0310162. [DOI] [PubMed] [Google Scholar]
  28. Kim EK, Miller I, Aja S, Landree LE, Pinn M, McFadden J, Kuhajda FP, Moran TH, Ronnett GV. C75, a fatty acid synthase inhibitor, reduces food intake via hypothalamic AMP-activated protein kinase. J Biol Chem. 2004a;279:19970–19976. doi: 10.1074/jbc.M402165200. [DOI] [PubMed] [Google Scholar]
  29. Kim MS, Park JY, Namkoong C, Jang PG, Ryu JW, Song HS, Yun JY, Namgoong IS, Ha J, Park IS, Lee IK, Viollet B, Youn JH, Lee HK, Lee KU. Anti-obesity effects of α-lipoic acid mediated by suppression of hypothalamic AMP-activated protein kinase. Nat Med. 2004b;10:727–733. doi: 10.1038/nm1061. [DOI] [PubMed] [Google Scholar]
  30. Kirkham TC. Endocannabinoids in the regulation of appetite and body weight. Behav Pharmacol. 2005;16:297–313. doi: 10.1097/00008877-200509000-00004. [DOI] [PubMed] [Google Scholar]
  31. Kola B, Hubina E, Tucci SA, Kirkham TC, Garcia EA, Mitchell SE, Williams LM, Hawley SA, Hardie DG, Grossman AB, Korbonits M. Cannabinoids and ghrelin have both central and peripheral metabolic and cardiac effects via AMP-activated protein kinase. J Biol Chem. 2005;280:25196–25201. doi: 10.1074/jbc.C500175200. [DOI] [PubMed] [Google Scholar]
  32. Landree LE, Hanlon AL, Strong DW, Rumbaugh G, Miller IM, Thupari JN, Connolly EC, Huganir RL, Richardson C, Witters LA, Kuhajda FP, Ronnett GV. C75, a fatty acid synthase inhibitor, modulates AMP-activated protein kinase to alter neuronal energy metabolism. J Biol Chem. 2004;279:3817–3827. doi: 10.1074/jbc.M310991200. [DOI] [PubMed] [Google Scholar]
  33. Lane MD, Hu Z, Cha SH, Dai Y, Wolfgang M, Sidhaye A. Role of malonyl-CoA in the hypothalamic control of food intake and energy expenditure. Biochem Soc Trans. 2005;33:1063–1067. doi: 10.1042/BST20051063. [DOI] [PubMed] [Google Scholar]
  34. Lee K, Li B, Xi X, Suh Y, Martin RJ. Role of neuronal energy status in the regulation of adenosine 5′-monophosphate-activated protein kinase, orexigenic neuropeptides expression, and feeding behavior. Endocrinology. 2005;146:3–10. doi: 10.1210/en.2004-0968. [DOI] [PubMed] [Google Scholar]
  35. Leff T. AMP-activated protein kinase regulates gene expression by direct phosphorylation of nuclear proteins. Biochem Soc Trans. 2003;31:224–227. doi: 10.1042/bst0310224. [DOI] [PubMed] [Google Scholar]
  36. Levin BE. Glucosensing neurons do more than just sense glucose. Int J Obes Relat Metab Disord. 2001;25(Suppl. 5):S68–S72. doi: 10.1038/sj.ijo.0801916. [DOI] [PubMed] [Google Scholar]
  37. Levin BE, Routh VH, Kang L, Sanders NM, Dunn-Meynell AA. Neuronal glucosensing: what do we know after 50 years. Diabetes. 2004;53:2521–2528. doi: 10.2337/diabetes.53.10.2521. [DOI] [PubMed] [Google Scholar]
  38. Lewen A, Matz P, Chan PH. Free radical pathways in CNS injury. J Neurotrauma. 2000;17:871–890. doi: 10.1089/neu.2000.17.871. [DOI] [PubMed] [Google Scholar]
  39. Loftus TM, Jaworsky DE, Frehywot GL, Townsend CA, Ronnett GV, Lane MD, Kuhajda FP. Reduced food intake and body weight in mice treated with fatty acid synthase inhibitors. Science. 2000;288:2379–2381. doi: 10.1126/science.288.5475.2379. [DOI] [PubMed] [Google Scholar]
  40. Luo Z, Saha AK, Xiang X, Ruderman NB. AMPK, the metabolic syndrome and cancer. Trends Pharmacol Sci. 2005;26:69–76. doi: 10.1016/j.tips.2004.12.011. [DOI] [PubMed] [Google Scholar]
  41. Marsin AS, Bertrand L, Rider MH, Deprez J, Beauloye C, Vincent MF, Van Den Berghe G, Carling D, Hue L. Phosphorylation and activation of heart PFK-2 by AMPK has a role in the stimulation of glycolysis during ischaemia. Curr Biol. 2000;10:1247–1255. doi: 10.1016/s0960-9822(00)00742-9. [DOI] [PubMed] [Google Scholar]
  42. McCrimmon RJ, Fan X, Ding Y, Zhu W, Jacob RJ, Sherwin RS. Potential role for AMP-activated protein kinase in hypoglycemia sensing in the ventromedial hypothalamus. Diabetes. 2004;53:1953–1958. doi: 10.2337/diabetes.53.8.1953. [DOI] [PubMed] [Google Scholar]
  43. McCullough LD, Zeng Z, Li H, Landree LE, McFadden J, Ronnett GV. Pharmacological inhibition of AMP-activated protein kinase provides neuroprotection in stroke. J Biol Chem. 2005;280:20493–20502. doi: 10.1074/jbc.M409985200. [DOI] [PubMed] [Google Scholar]
  44. Merrill GF, Kurth EJ, Hardie DG, Winder WW. AICA riboside increases AMP-activated protein kinase, fatty acid oxidation, and glucose uptake in rat muscle. Am J Physiol. 1997;273:E1107–E1112. doi: 10.1152/ajpendo.1997.273.6.E1107. [DOI] [PubMed] [Google Scholar]
  45. Minokoshi Y, Alquier T, Furukawa N, Kim YB, Lee A, Xue B, Mu J, Foufelle F, Ferre P, Birnbaum MJ, Stuck BJ, Kahn BB. AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. Nature. 2004;428:569–574. doi: 10.1038/nature02440. [DOI] [PubMed] [Google Scholar]
  46. Minokoshi Y, Kim YB, Peroni OD, Fryer LG, Muller C, Carling D, Kahn BB. Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase. Nature. 2002;415:339–343. doi: 10.1038/415339a. [DOI] [PubMed] [Google Scholar]
  47. Moore F, Brophy PJ. Regulation of acetyl-CoA carboxylase (ACC) by ATP depletion in developing oligodendrocytes mimics the action of AMP-activated protein kinase (AMPK) Biochem Soc Trans. 1994;22:416S. doi: 10.1042/bst022416s. [DOI] [PubMed] [Google Scholar]
  48. Mu J, Brozinick J, Joseph T, Valladares O, Bucan M, Birnbaum MJ. A role for AMP-activated protein kinase in contraction- and hypoxia-regulated glucose transport in skeletal muscle. Mol Cell. 2001;7:1085–1094. doi: 10.1016/s1097-2765(01)00251-9. [DOI] [PubMed] [Google Scholar]
  49. Namkoong C, Kim MS, Jang PG, Han SM, Park HS, Koh EH, Lee WJ, Kim JY, Park IS, Park JY, Lee KU. Enhanced hypothalamic AMP-activated protein kinase activity contributes to hyperphagia in diabetic rats. Diabetes. 2005;54:63–68. doi: 10.2337/diabetes.54.1.63. [DOI] [PubMed] [Google Scholar]
  50. Obici S, Feng Z, Arduini A, Conti R, Rossetti L. Inhibition of hypothalamic carnitine palmitoyltransferase-1 decreases food intake and glucose production. Nat Med. 2003;9:756–761. doi: 10.1038/nm873. [DOI] [PubMed] [Google Scholar]
  51. Pertsch M, Duncan GE, Stumpf WE, Pilgrim C. A histochemical study of the regional distribution in the rat brain of enzymatic activity hydrolyzing glucose- and 2-deoxyglucose-6-phosphate. Histochemistry. 1988;88:257–262. doi: 10.1007/BF00570281. [DOI] [PubMed] [Google Scholar]
  52. Rowan A, Churchman M, Jefferey R, Hanby A, Poulsom R, Tomlinson I. In situ analysis of LKB1/STK11 mRNA expression in human normal tissues and tumours. J Pathol. 2000;192:203–206. doi: 10.1002/1096-9896(2000)9999:9999<::AID-PATH686>3.0.CO;2-J. [DOI] [PubMed] [Google Scholar]
  53. Ruderman NB, Saha AK, Kraegen EW. Minireview: Malonyl CoA, AMP-activated protein kinase, and adiposity. Endocrinology. 2003;144:5166–5171. doi: 10.1210/en.2003-0849. [DOI] [PubMed] [Google Scholar]
  54. Ruderman NB, Saha AK, Vavvas D, Witters LA. Malonyl-CoA, fuel sensing, and insulin resistance. Am J Physiol. 1999;276:E1–E18. doi: 10.1152/ajpendo.1999.276.1.E1. [DOI] [PubMed] [Google Scholar]
  55. Russell RR III, Li J, Coven DL, Pypaert M, Zechner C, Palmeri M, Giordano FJ, Mu J, Birnbaum MJ, Young LH. AMP-activated protein kinase mediates ischemic glucose uptake and prevents postischemic cardiac dysfunction, apoptosis, and injury. J Clin Invest. 2004;114:495–503. doi: 10.1172/JCI19297. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Sakagami H, Saito S, Kitani T, Okuno S, Fujisawa H, Kondo H. Localization of the mRNAs for two isoforms of Ca2+/calmodulin-dependent protein kinase kinases in the adult rat brain. Brain Res Mol Brain Res. 1998;54:311–315. doi: 10.1016/s0169-328x(97)00362-8. [DOI] [PubMed] [Google Scholar]
  57. Sakamoto K, McCarthy A, Smith D, Green KA, Hardie GD, Ashworth A, Alessi DR. Deficiency of LKB1 in skeletal muscle prevents AMPK activation and glucose uptake during contraction. EMBO J. 2005;24:1810–1820. doi: 10.1038/sj.emboj.7600667. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Shaw RJ, Kosmatka M, Bardeesy N, Hurley RL, Witters LA, DePinho RA, Cantley LC. The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress. Proc Natl Acad Sci U S A. 2004;101:3329–3335. doi: 10.1073/pnas.0308061100. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Shaw RJ, Lamia KA, Vasquez D, Koo SH, Bardeesy N, Depinho RA, Montminy M, Cantley LC. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science. 2005;310:1642–1646. doi: 10.1126/science.1120781. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Spanswick D, Smith MA, Groppi VE, Logan SD, Ashford ML. Leptin inhibits hypothalamic neurons by activation of ATP-sensitive potassium channels. Nature. 1997;390:521–525. doi: 10.1038/37379. [DOI] [PubMed] [Google Scholar]
  61. Spanswick D, Smith MA, Mirshamsi S, Routh VH, Ashford ML. Insulin activates ATP-sensitive K+ channels in hypothalamic neurons of lean, but not obese rats. Nat Neurosci. 2000;3:757–758. doi: 10.1038/77660. [DOI] [PubMed] [Google Scholar]
  62. Stapleton D, Mitchelhill KI, Gao G, Widmer J, Michell BJ, Teh T, House CM, Fernandez CS, Cox T, Witters LA, Kemp BE. Mammalian AMP-activated protein kinase subfamily. J Biol Chem. 1996;271:611–614. doi: 10.1074/jbc.271.2.611. [DOI] [PubMed] [Google Scholar]
  63. Stein SC, Woods A, Jones NA, Davison MD, Carling D. The regulation of AMP-activated protein kinase by phosphorylation. Biochem J. 2000;345:437–443. [PMC free article] [PubMed] [Google Scholar]
  64. Thupari JN, Landree LE, Ronnett GV, Kuhajda FP. C75 increases peripheral energy utilization and fatty acid oxidation in diet-induced obesity. Proc Natl Acad Sci U S A. 2002;99:9498–9502. doi: 10.1073/pnas.132128899. [DOI] [PMC free article] [PubMed] [Google Scholar]
  65. Turnley AM, Stapleton D, Mann RJ, Witters LA, Kemp BE, Bartlett PF. Cellular distribution and developmental expression of AMP-activated protein kinase isoforms in mouse central nervous system. J Neurochem. 1999;72:1707–1716. doi: 10.1046/j.1471-4159.1999.721707.x. [DOI] [PubMed] [Google Scholar]
  66. Vavvas D, Apazidis A, Saha AK, Gamble J, Patel A, Kemp BE, Witters LA, Ruderman NB. Contraction-induced changes in acetyl-CoA carboxylase and 5′-AMP-activated kinase in skeletal muscle. J Biol Chem. 1997;272:13255–13261. doi: 10.1074/jbc.272.20.13255. [DOI] [PubMed] [Google Scholar]
  67. Wang R, Liu X, Hentges ST, Dunn-Meynell AA, Levin BE, Wang W, Routh VH. The regulation of glucose-excited neurons in the hypothalamic arcuate nucleus by glucose and feeding-relevant peptides. Diabetes. 2004;53:1959–1965. doi: 10.2337/diabetes.53.8.1959. [DOI] [PubMed] [Google Scholar]
  68. Williams G, Bing C, Cai XJ, Harrold JA, King PJ, Liu XH. The hypothalamus and the control of energy homeostasis: different circuits, different purposes. Physiol Behav. 2001;74:683–701. doi: 10.1016/s0031-9384(01)00612-6. [DOI] [PubMed] [Google Scholar]
  69. Winder WW, Hardie DG. Inactivation of acetyl-CoA carboxylase and activation of AMP-activated protein kinase in muscle during exercise. Am J Physiol. 1996;270:E299–E304. doi: 10.1152/ajpendo.1996.270.2.E299. [DOI] [PubMed] [Google Scholar]
  70. Witters LA, Kemp BE, Means AR. Chutes and Ladders: the search for protein kinases that act on AMPK. Trends Biochem Sci. 2006;31:13–16. doi: 10.1016/j.tibs.2005.11.009. [DOI] [PubMed] [Google Scholar]
  71. Woods A, Dickerson K, Heath R, Hong SP, Momcilovic M, Johnstone SR, Carlson M, Carling D. Ca2+/calmodulin-dependent protein kinase kinase-β acts upstream of AMP-activated protein kinase in mammalian cells. Cell Metab. 2005;2:21–33. doi: 10.1016/j.cmet.2005.06.005. [DOI] [PubMed] [Google Scholar]
  72. Woods A, Johnstone SR, Dickerson K, Leiper FC, Fryer LG, Neumann D, Schlattner U, Wallimann T, Carlson M, Carling D. LKB1 is the upstream kinase in the AMP-activated protein kinase cascade. Curr Biol. 2003;13:2004–2008. doi: 10.1016/j.cub.2003.10.031. [DOI] [PubMed] [Google Scholar]
  73. Yamauchi T, Kamon J, Minokoshi Y, Ito Y, Waki H, Uchida S, Yamashita S, Noda M, Kita S, Ueki K, Eto K, Akanuma Y, Froguel P, Foufelle F, Ferre P, Carling D, Kimura S, Nagai R, Kahn BB, Kadowaki T. Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat Med. 2002;8:1288–1295. doi: 10.1038/nm788. [DOI] [PubMed] [Google Scholar]
  74. Young LH, Li J, Baron SJ, Russell RR. AMP-activated protein kinase: a key stress signaling pathway in the heart. Trends Cardiovascular Med. 2005;15:110–118. doi: 10.1016/j.tcm.2005.04.005. [DOI] [PubMed] [Google Scholar]

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